product information orencia (abatacept) (lyophilized ... · included an iv loading dose, however,...

AU_PI_V5.0_15 August 2012 1

PRODUCT INFORMATION

ORENCIA® (abatacept)

(LYOPHILIZED POWDER FOR IV INFUSION)

(SOLUTION FOR SUBCUTANEOUS ADMINISTRATION)

NAME OF THE MEDICINE ORENCIA® (abatacept (rch)) ORENCIA® (abatacept (rch)). Abatacept is a costimulation modulator of the interaction of CD80 and CD86 on antigen presenting cells with CD28 on T-lymophocytes. Abatacept is a soluble fusion protein that consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to the modified Fc (hinge, CH2, and CH3 domains) portion of human immunoglobulin G1. Abatacept is produced by recombinant DNA technology in Chinese hamster ovary cells. The apparent molecular weight of abatacept is 92 kilodaltons.

Abatacept structure:

CAS number 3 332348-12-6

DESCRIPTION ORENCIA® powder for intravenous infusion is supplied as a sterile, white, preservative-free, lyophilized powder for parenteral administration. Following reconstitution of the lyophilized powder with 10 mL of sterile water for injection, the solution of ORENCIA ® is clear, colorless to pale yellow, with a pH range of 7.2 to 7.8. Each single-use vial provides 250 mg abatacept, 500 mg maltose, 17.2 mg sodium phosphate monobasic and 14.6 mg of sodium chloride.

ORENCIA®, solution for injection, pre-filled syringe is supplied as a sterile, single-dose, preservative-free, ready-to-use solution for subcutaneous injection. The subcutaneous solution is clear, colorless to pale yellow with a pH of 6.8 to 7.4. Each single dose of subcutaneous injection

C92

C21

C231

C21

C92C48

C120-C120

C48

C66C66

C171 C171

C335C335

C277

C231

C277

N108N108

N-76N76

N207 N207

S129S129

S139S139

CTLA4 region

Fc region

Disulfide Bonds

N-linked oligosaccharide

O-linked oligosaccharide

C92

C21

C231

C21

C92C48

C120-C120

C48

C66C66

C171 C171

C335C335

C277

C231

C277

N108N108

N-76N76

N207 N207

S129S129

S139S139

CTLA4 region

Fc region

Disulfide Bonds

N-linked oligosaccharide

O-linked oligosaccharide


provides 125 mg abatacept, 170 mg sucrose, 8 mg poloxamer 188, 0.286 mg sodium phosphate monobasic, 0.838 mg sodium phosphate dibasic anhydrous, and up to 1 mL water for injection. ORENCIA® solution for subcutaneous administration contains no maltose.

PHARMACOLOGY General Abatacept modulates a key costimulatory signal required for full activation of T lymphocytes expressing CD28. T lymphocytes are found in the synovium of patients with RA. Activated T lymphocytes contribute to the pathogenesis of RA and other autoimmune diseases. Full activation of T lymphocytes requires two signals provided by antigen presenting cells: recognition of a specific antigen by a T cell receptor (signal 1) and a second, costimulatory signal. A major costimulatory pathway involves the binding of CD80 and CD86 molecules on the surface of antigen presenting cells to the CD28 receptor on T lymphocytes (signal 2). Abatacept binds specifically to CD80 and CD86 inhibiting this costimulatory pathway. Studies indicate that abatacept affects both memory and naïve T lymphocyte responses.

Studies in vitro and in animal models demonstrate that abatacept attenuates T lymphocyte dependent antibody responses and inflammation. In vitro, abatacept attenuates T lymphocyte activation as measured by decreased proliferation and cytokine production in human lymphocytes. Abatacept decreases antigen specific TNFα, interferon-γ, and interleukin-2 production by T lymphocytes. In a rat collagen-induced arthritis model, abatacept suppresses inflammation, decreases anti-collagen antibody production and reduces antigen specific production of interferon-γ.

Pharmacodynamics Dose finding studies were conducted with abatacept monotherapy (placebo, 0.5 mg/kg, 2 mg/kg, and 10 mg/kg) and in combination with MTX (placebo, 2 mg/kg, and 10 mg/kg). In both studies, the American College of Rheumatology (ACR) 20 response rate increased with increasing doses at 2 mg/kg and 10 mg/kg. In clinical trials with ORENCIA® using doses approximating 10 mg/kg, inhibition of T lymphocyte activation, decreases in products of macrophages, fibroblast-like synoviocytes, and B cells, and reductions in acute phase reactants of inflammation were observed. Decreases were seen in: serum levels of soluble interleukin-2 receptor, a marker of T lymphocyte activation; serum interleukin-6, a product of activated macrophages and fibroblast-like synoviocytes; rheumatoid factor, an autoantibody produced by plasma cells; and C-reactive protein, an acute phase reactant of inflammation. In addition, serum levels of matrix metalloproteinase-3, which produces cartilage destruction and tissue remodeling, were decreased. Reductions in serum TNFα were also observed. These changes are consistent with the mechanism of action of this selective costimulation modulator.

Pharmacokinetics Healthy adults and adult RA – Intravenous Infusion Absorption Abatacept is administered intravenously.

Distribution The pharmacokinetics of abatacept were studied in healthy adult subjects after a single 10 mg/kg intravenous infusion and in RA patients after multiple 10 mg/kg intravenous infusions (see Table 1).


Table 1: Pharmacokinetic Parameters (Mean, Range) in Healthy Subjects and RA Patients After 10 mg/kg Intravenous Infusion(s)

PK Parameter

Healthy Subjects (After 10 mg/kg Single Dose)

n=13

RA Patients (After 10 mg/kg Multiple Dosesa)

n=14

Peak Concentration (Cmax) [mcg/mL] 292 (175-427) 295 (171-398)

Terminal half-life (t1/2) [days] 16.7 (12-23) 13.1 (8-25)

Systemic clearance (CL) [mL/h/kg] 0.23 (0.16-0.30) 0.22 (0.13-0.47)

Volume of distribution (Vss) [L/kg] 0.09 (0.06-0.13) 0.07 (0.02-0.13) a Multiple intravenous infusions were administered at days 1, 15, 30, and monthly thereafter.

The pharmacokinetics of abatacept in RA patients and healthy subjects appeared to be comparable. In RA patients, after multiple intravenous infusions, the pharmacokinetics of abatacept showed proportional increases of Cmax and AUC over the dose range of 2 mg/kg to 10 mg/kg. At 10 mg/kg, serum concentration appeared to reach a steady-state by day 60 with a mean (range) trough concentration of 24 (1-66) mcg/mL. No systemic accumulation of abatacept occurred upon continued repeated treatment with 10 mg/kg at monthly intervals in RA patients.

Population pharmacokinetic analyses in RA patients revealed that there was a trend toward higher clearance of abatacept with increasing body weight. Age and gender (when corrected for body weight) did not affect clearance. Concomitant MTX, NSAIDs, corticosteroids, and TNF blocking agents did not influence abatacept clearance.

Adult RA - Subcutaneous Administration Abatacept exhibited linear pharmacokinetics following subcutaneous administration. The mean (range) for Cmin and Cmax at steady state observed after 85 days of treatment was 32.5 mcg/mL (6.6 to 113.8 mcg/mL) and 48.1 mcg/mL (9.8 to 132.4 mcg/mL), respectively. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. Mean estimates for systemic clearance (0.28 mL/h/kg), volume of distribution (0.11 L/kg), and terminal half-life (14.3 days) were comparable between SC and IV administration.

A single study was conducted to determine the effect of monotherapy use of abatacept on immunogenicity following subcutaneous administration without an IV load. When the IV loading dose was not administered, a mean trough concentration of 12.6 mcg/mL was achieved after 2 weeks of dosing. The efficacy response over time in this study appeared consistent with studies that included an IV loading dose, however, the effect of no IV load on the onset of efficacy has not been formally studied.

Consistent with the IV data, population pharmacokinetic analyses for SC abatacept in RA patients revealed that there was a trend toward higher clearance of abatacept with increasing body weight. Age and gender (when corrected for body weight) did not affect apparent clearance. Concomitant MTX, NSAIDs, corticosteroids, and TNF blocking agents did not influence abatacept apparent clearance.

Metabolism and elimination

Studies were not carried out to evaluate the metabolism or elimination of abatacept in humans. Owing to steric and hydrophilic considerations, abatacept would not be metabolized by liver


cytochrome P450 enzymes. Because of its large molecular weight abatacept is not expected to undergo renal elimination.

Special populations Paediatric and Adolescent Patients. Population pharmacokinetic analysis of abatacept serum concentration data from patients with juvenile idiopathic arthritis (JIA) aged 6 to 17 years following administration of abatacept 10 mg/kg revealed that the estimated clearance of abatacept, when normalized for baseline body weight, was higher in JIA patients (0.44 ml/h/kg) versus adult RA patients. After accounting for the effect of body weight, the clearance of abatacept was not related to age or gender. Mean estimates for distribution volume and elimination half-life were 0.12 l/kg and 11.2 days, respectively. As a result of the higher body-weight normalized clearance in JIA patients, the predicted systemic exposure of abatacept was lower than that observed in adults, such that the observed mean (range) peak and trough concentrations were 217 (57 to 700) and 11.9 (0.15 to 44.6) mcg/mL, respectively. Administration of other concomitant medications such as methotrexate, corticosteroids, and NSAIDs did not influence the clearance of abatacept in JIA patients.

No formal studies were conducted to examine the effects of either renal or hepatic impairment on the pharmacokinetics of abatacept. Thus both the long-term safety and effectiveness of abatacept in children with renal or hepatic impairment are also unknown. The use of abatacept in this special population is not recommended.

CLINICAL TRIAL EFFICACY INFORMATION Adult Rheumatoid Arthritis in Patients treated with intravenous ORENCIA ®

Clinical trials The efficacy and safety of ORENCIA® for intravenous administration were assessed in six randomized, double-blind, placebo-controlled studies in patients ≥ age 18 with active RA diagnosed according to American College of Rheumatology (ACR) criteria. The trials are designated as follows: Study I (IM103002), Study II (IM101100), Study III (IM101102, AIM), Study IV (IM101029, ATTAIN), Study V (IM101031, ASSURE) and Study VI (IM101023, AGREE). Studies I, II, III, IV and VI required patients to have at least 12 tender and 10 swollen joints at randomization. Study V did not require any specific number of tender or swollen joints. ORENCIA® or placebo treatment was given intravenously at weeks 0, 2, and 4 and then every 4 weeks thereafter.

Study I, a supportive study, evaluated ORENCIA® as monotherapy in 122 patients with active RA who had failed at least one non-biologic DMARD or etanercept. In Study II and Study III, the efficacy and safety of ORENCIA® were assessed in patients with an inadequate response to MTX and who were continued on their stable dose of MTX. In Study IV, the efficacy and safety of ORENCIA® were assessed in patients with an inadequate response to a TNF blocking agent, with the TNF blocking agent discontinued prior to randomization; other DMARDs were permitted. Study V primarily assessed safety in patients with active RA requiring additional intervention in spite of current therapy with DMARDs; all DMARDs used at enrollment were continued. In Study VI, the efficacy and safety of ORENCIA® were assessed in MTX-naive patients with early, erosive RA (≤2 years disease duration). In Study VI, patients previously naive to MTX were randomized to receive ORENCIA® plus MTX or MTX plus placebo.

In Study VI, the efficacy and safety of abatacept were assessed in methotrexate-naive, Rheumatoid Factor (RF) and/or anti-Cyclic Citrullinated Peptide 2 (Anti-CCP2)-positive patients with early, erosive rheumatoid arthritis (≤ 2 years disease duration) who were randomized to receive abatacept


plus methotrexate or methotrexate plus placebo. For all patients randomized and treated, the median age was 51 years, the median disease duration was 3 months and the median tender and swollen joint counts were 28 and 20, respectively. Patients were randomized to receive abatacept (10 mg/kg,

weight-tiered dose) plus MTX or MTX plus placebo for the first 12 months of treatment. In both groups, the MTX dose was titrated to at least 15 mg per week not to exceed 20 mg per week. The co-primary endpoints of this study were the proportion of subjects in abatacept+MTX group versus placebo+MTX who achieved DAS-28-CRP remission and to compare inhibition of joint damage progression measured by the Genant-modified Sharp total score at 12 months of treatment.

Study I patients were randomized to receive one of three doses of ORENCIA® (0.5, 2, or 10 mg/kg) or placebo ending at week 8. Study II patients were randomized to receive ORENCIA® 2 or 10 mg/kg or placebo for 12 months. For studies I and II, only results in the 10mg/kg group are discussed below. Study III, IV, V and VI patients were randomized to receive a fixed dose approximating 10 mg/kg of ORENCIA® or placebo for 12 months (Studies III V and VI) or 6 months (Study IV). The dose of ORENCIA® was 500 mg for patients weighing less than 60 kg, 750 mg for patients weighing 60 to 100 kg, and 1 gram for patients weighing greater than 100 kg.

Clinical response ACR response The percent of ORENCIA®-treated patients achieving ACR 20, 50, and 70 responses and major clinical response (defined as achieving an ACR 70 response for a continuous 6-month period) in Studies III IV and VI are shown in Table 2. Month 6 and 12 ACR response rates in Study II for the 10 mg/kg group were similar to the ORENCIA® group in Study III. ACR response rates at 3 months in Study I were supportive of these findings.

In Studies III and IV, improvement in the ACR 20 response rate versus placebo was observed after administration of the first dose, as measured at day 15, and was maintained through the double-blind study period. In Study VI, improvement in the ACR 20 response rate in ORENCIA®+MTX-treated patients versus MTX+placebo-treated patients was observed at 29 days, and was maintained through the double-blind study period. The ACR 50 response with ORENCIA® was significantly greater than placebo at months 2 and 3, respectively, for Studies III IV and VI, with continued improvement in the ACR50 response rate through the double-blind period (month 12 in Study III and month 6 in Study IV). In the placebo-controlled periods of Studies II, III and VI, ACR response rates were maintained to 12 months in ORENCIA®-treated patients. In the uncontrolled open-label long-term extension of Studies II, III, IV and VI, durable and sustained ACR 20, 50, and 70 responses have been observed through 7 years, 5 years, and 2 years, respectively, of ORENCIA® treatment based on as-observed analyses.

In study II, ACR responses were assessed at 7 years with 31/43 (72%) ACR 20 responses, 25/43 (58%) ACR 50 responses, and 19/43 ( 44%) ACR 70 responses. In study III, ACR responses were assessed at 5 years with 224/268 (84%) ACR 20 responses, 165/270 ( 61%) ACR 50 responses, and 107/270 ( 40%) ACR 70 responses. In study IV, ACR responses were assessed at 5 years with 66/89 (74%) ACR 20 responses, 45/88 (51%) ACR 50 responses, and 21/ 91 (23%) ACR 70 responses. In study VI, ACR responses were assessed at 2 years with 196/219 (90%) ACR 20 responses, 169/217 (78%) ACR 50 responses, and 124/216 (57%) ACR 70 responses.

Greater improvement was seen in all ACR response criteria components in ORENCIA®-treated patients than in placebo-treated patients through 6 (Study IV) and 12 (Study II and III) months. In Study VI, greater improvement was seen in all ACR components at 12 months in ORENCIA®+MTX-treated patients than in MTX+placebo-treated patients. In the open-label extension of Studies II, III, and IV, improvements in the individual ACR components were maintained through 7, 5, and 5 years, respectively, of ORENCIA® treatment.


Table 2: Clinical Responses in Controlled Trials

Percent of Patients

Intravenous Administration Subcutaneous Administration

Inadequate Response to MTX

Inadequate Response to TNF Blocking Agent

MTX-Naive Inadequate Response to MTX

Study III Study IV Study VI Study SC-I,

Response Rate

Abatacepta

+MTX n=424

Placebo +MTX n=214

Abatacepta+ DMARDsb

n=256

Placebo + DMARDsb

n=133

Abatacepta +MTX n=256

Placebo +MTX n=253

Abatacepte SC

+MTX n=693

Abatacepte IV

+MTX n=678

ACR 20 Month 3 62%*** 37% 46%*** 18% 64%* 53% 68% 69% Month 6 68%*** 40% 50%*** 20% 75%** 62% 76%§ 76% Month 12 73%*** 40% NA NA 76%*** 62% NA NA

ACR 50 Month 3 32%*** 8% 18%** 6% 40%*** 23% 33% 39% Month 6 40%*** 17% 20%*** 4% 53%*** 38% 52% 50% Month 12 48%*** 18% NA NA 57%*** 42% NA NA

ACR 70 Month 3 13%*** 3% 6%* 1% 19%** 10% 13% 16% Month 6 20%*** 7% 10%** 2% 32%** 20% 26% 25% Month 12 29%*** 6% NA NA 43%*** 27% NA NA

Major Clinical Responsec

14%*** 2% NA NA 27%*** 12% NA NA

DAS28-CRP Remission <2.6d

Month 12 NA NA NA NA 41%*** 23% NA NA * p<0.05, ORENCIA® vs placebo or ORENCIA®+MTX vs MTX+placebo (Study VI). ** p<0.01, ORENCIA® vs placebo or ORENCIA®+MTX vs MTX+placebo (Study VI) *** p<0.001, ORENCIA® vs placebo or ORENCIA®+MTX vs MTX+placebo (Study VI). § 95% CI: −4.2, 4.8 (based on prespecified margin for non-inferiority of −7.5%) a Fixed dose approximating 10 mg/kg. b Concurrent DMARDs included one or more of the following: MTX, azathioprine,

chloroquine/hydroxychloroquine, gold, leflunomide, sulfasalazine, and anakinra. c Major clinical response is defined as achieving an ACR 70 response for a continuous 6-month period d DAS28-CRP Remission is defined as a DAS28-CRP score <2.6 e Per protocol data is presented in table. For ITT; n=736, 721 for SC and IV Orencia®, respectively

Among ORENCIA®-treated patients in Study III, 14% achieved a major clinical response, as compared with 2% in placebo patients. In addition, 6% of ORENCIA®-treated patients in this 12-month study achieved an extended major clinical response (continuous ACR 70 response over 9 months), as compared with 0.5% in placebo patients. In Study III, for patients treated with ORENCIA® over two years including double-blind and open-label periods, the percentage of subjects achieving a major clinical response and an extended major clinical response increased to 34.3% and 24.5%, respectively.


ORENCIA®-treated patients experienced greater improvement than placebo-treated patients in morning stiffness.

DAS28 remission Disease activity was also assessed using the Disease Activity Score 28 (DAS28). In Studies III and IV, the baseline mean DAS28 was 6.8 and 6.9 units, respectively, representing a high degree of disease activity. In Study II, the mean improvement in DAS28 at 12 months in ORENCIA® -treated patients of 2.9 was significantly greater than the mean improvement of 1.5 observed in placebo-treated patients. DAS28 defined remission was achieved in 17% of ORENCIA® -treated patients compared to 2% of placebo-treated patients at 12 months. In Study IV, at month 6, a significantly greater improvement in DAS28 was observed in the ORENCIA® -treated patients than in placebo-treated patients (reduction of 2.0 vs. 0.7 units respectively, DAS28-defined remission was achieved in 10% of ORENCIA® -treated patients compared to 1% of placebo-treated patients at 6 months. In Study VI, patients treated with ORENCIA plus MTX had a higher DAS28-CRP remission rate at 12 months than those treated with MTX plus placebo (Table 2). Of patients treated with ORENCIA plus MTX who achieved DAS28-CRP remission, 54% had no active joints, 17% had one active joint, 7% had two active joints, and 22% had three or more active joints, where an active joint was a joint that was rated as tender or swollen or both.

Radiographic response Structural joint damage was assessed radiographically over a two-year period in Study III in RA patients with inadequate response to MTX. The results were measured using the Genant-modified Total Sharp score (TSS) and its components, the erosion score and Joint Space Narrowing (JSN) score. The baseline median TSS was 31.7 in ORENCIA®-treated patients and 33.4 in placebo-treated patients. In the first year, patients received ORENCIA® or placebo in double-blind fashion. ORENCIA®/MTX inhibited the progression of structural damage compared to placebo/MTX after 12 months of treatment as shown in Table 3.

Inhibition of progression of structural damage with ORENCIA® was observed regardless of disease duration (less than 2 years, 2 to 5 years, 5 to 10 years, and greater than 10 years).

Table 3: Mean Radiographic Changes Over 12 Months in Study III

Parameter ORENCIA®/MTX

n=391 Placebo/MTX

n=195

P-valuea

Total Sharp score 1.21 2.32 0.012

Erosion score 0.63 1.14 0.029

JSN score 0.58 1.18 0.009 a Based on non-parametric analysis.

In the open-label extension of Study III, 75% (n = 324) of patients initially randomized to ORENCIA®/MTX were evaluated radiographically by the TSS. Following 2 years of treatment with ORENCIA®/MTX, inhibition of progression of structural damage was observed. Fifty (50) percent of the patients had no progression of structural damage as defined by a change in the TSS of zero or less at 2 years. Eighty-six (86) percent of patients with no radiographic progression after 1 year of treatment with ORENCIA®/MTX, had no progression at 2 years. For patients treated with ORENCIA®/MTX, the mean change in TSS from year 1 to year 2 was 57% lower than the mean change in TSS from baseline to year 1.

Based on year-to-year assessment, a decrease in radiographic progression was observed for all 3 scores with the most decrease observed in the first year of the abatacept treatment in the


uncontrolled, open-label, long-term (LT) period. At the end of the LT period (4 years, Day 1821), 106/235 (45.1%) subjects in the original abatacept group and 45/115 (39.1%) subjects in the original placebo group showed no radiographic progression based on the Total score). In Study VI, the mean change in TSS at 12 months was significantly lower in patients treated with ORENCIA plus MTX compared to those treated with MTX plus placebo. At 12 months 61% (148/242) of the patients treated with abatacept plus methotrexate and 53% (128/242) of the patients treated with methotrexate plus placebo had no progression (change from baseline in TSS ≤ 0). Among the patients who entered the open-label 12 month period, the progression of structural damage was lower in those receiving continuous abatacept plus methotrexate treatment (for 24 months) compared to patients who initially received methotrexate plus placebo (for 12 months) and were switched to abatacept plus methotrexate for the next 12 months. Of these patients, 57% (121/213) who received continuous abatacept plus methotrexate treatment and 44% (84/192) of patients who initially received methotrexate and switched to combination with abatacept had no progression. Table 4: Mean Radiographic Changes Over 12 and 24 Months in Study VI

Month 12 Month 24 Parameter ORENCIA®/

MTX n= 242

Placebo /MTX n= 242

P-valuea

ORENCIA®/ MTX n= 213

Placebo /MTX n= 192

Total Sharp score Baseline (Mean) 7.50 6.67 7.73 7.24 Change from Baseline (Mean) 0.63 1.06 0.040 0.84 1.75

Erosion score Baseline (Mean) 5.48 4.81 5.91 5.49 Change from Baseline (Mean) 0.50 0.89 0.033 0.59 1.40

JSN score Baseline (Mean) 2.03 1.86 1.83 1.75 Change from Baseline (mean) 0.13 0.17 0.353 0.25 0.34 a Based on non-parametric analysis.

The effect of ORENCIA® on structural damage was not studied in RA patients with an inadequate response to TNF blocking agents.

Physical function response Improvement in physical function was measured by the Health Assessment Questionnaire Disability Index (HAQ-DI) in Studies III, IV, and V, and a modified HAQ-DI in Study II. In Studies II-V, ORENCIA® demonstrated significantly greater improvement from baseline than placebo in the HAQ-DI and a significantly greater proportion of patients treated with ORENCIA® compared to placebo showed a clinically meaningful improvement (reduction in HAQ-DI of ≥0.3 units from baseline). In Study VI, significantly greater improvement from baseline in the HAQ-DI was observed in ORENCIA+MTX-treated patients compared with MTX+placebo-treated patients, and significantly more patients in the ORENCIA+MTX group compared with the MTX+placebo group achieved a clinically meaningful improvement at 12 months. In Study III, among HAQ responders at month 12, 88% retained the response at month 18, and 85% retained the response at month 24. The results from Studies II-IV are shown in Table 5. During the open-label periods of Studies II, III, IV, and VI, the improvement in physical function has been maintained through 7 years, 5 years, 5 years, and 2 years, respectively.


Table 5: Mean Improvement from Baseline in Health Assessment

Questionnaire Disability Index (HAQ-DI)

Inadequate Response to Methotrexate (MTX)

Inadequate Response to TNF Blocking Agent

Study II Study III Study IV

HAQ Disability Index

ORENCIA® a +MTX

Placebo +MTX

ORENCIA® b +MTX

Placebo +MTX

ORENCIA® b +DMARDsc

Placebo +DMARDsc

Baseline (Mean)

0.98d (n=115)

0.97d (n=119)

1.69e

(n=422) 1.69e

(n=212) 1.83e

(n=249) 1.82e

(n=130)

Mean Improvement from Baseline Month 6

0.40d,*** (n=113)

0.19d (n=118)

0.59e,*** (n=420)

0.40e (n=211)

0.45e,*** (n=249)

0.11e (n=130)

Month 12 0.40d,*** (n=115)

0.15d (n=119)

0.66e,*** (n=422)

0.37e (n=212)

NA NA

Proportion of patients with a clinically meaningful improvementf Month 6

47%d,**

28%d

61%e,***

45%e

47%e,***

23%e

Month 12 38%d,** 20%d 64%e,*** 39%e NA NA

** p <0.01, ORENCIA® vs. placebo. *** p <0.001, ORENCIA® vs. placebo. a 10 mg/kg. b Fixed dose approximating 10 mg/kg.

c Concurrent DMARDs included one or more of the following: MTX, azathioprine, chloroquine/hydroxychloroquine, gold, leflunomide, sulfasalazine, and anakinra.

d Modified Health Assessment Questionnaire; 0 = best, 3 = worst; 8 questions; 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities.

e Health Assessment Questionnaire; 0 = best, 3 = worst; 20 questions; 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities.

f Reduction in HAQ-DI of ≥0.3 units from baseline.

Health-related outcomes and quality of life Health-related quality of life was assessed by the SF-36 questionnaire at 6 months in Studies II, III, and IV and at 12 months in Studies II and III. In these studies, clinically and statistically significant improvement was observed in the ORENCIA® group as compared with the placebo group in all 8 domains of the SF-36 (4 physical domains: physical function, role physical, bodily pain, general health; and 4 mental domains: vitality, social function, role emotional, mental health), as well as the Physical Component Summary (PCS) and the Mental Component Summary (MCS). In Study VI, improvement was observed at 12 months in the ORENCIA+MTX group as compared with the MTX+placebo group in both PCS and MCS and was maintained through 24 months.

In Studies III and IV, fatigue was measured by a validated Fatigue Visual Analogue Scale, and sleep problems were assessed by the Sleep Problems Index (SPI) of the Medical Outcomes Study Sleep Module. At 12 months and 6 months, in Study III and Study IV, respectively, statistically

AU_PI_V5.0_15 August 2012 10

significant reductions in fatigue and sleep problems were observed in ORENCIA®-treated patients as compared to placebo-treated patients. In Study VI, a greater reduction in the fatigue score was observed at 6 and 12 months in ORENCIA+MTX-treated patients than in MTX+placebo-treated patients. In open-label therapy with ORENCIA®, improvements in health-related outcomes and quality of life have been maintained for up to 4 years.

Additional clinical trials in adult rheumatoid arthritis. Study VII: abatacept or infliximab versus placebo A randomized, double blind study was conducted to assess the safety and efficacy of abatacept or infliximab versus placebo in patients with an inadequate response to methotrexate (Study VII, Study IM101043). Study VII patients received the same fixed dose of abatacept as that in Studies III-VI or 3 mg/kg infliximab or placebo for 6 months. Study VII continued for an additional 6 months with the abatacept and infliximab groups only. The primary outcome was the mean change in disease activity in abatacept-treated patients compared to placebo-treated patients at 6 months with a subsequent double-blind assessment of safety and efficacy of abatacept and infliximab at 12 months. The number of patients randomized was 156 to abatacept, 165 to infliximab, and 110 to placebo. In Study VII, the DAS28 mean changes from baseline at months 6 and 12 are shown in Table 6, as are the percentages of patients achieving DAS28-defined low disease activity and remission. Greater improvement (p < 0.001) in DAS28 was observed with abatacept and with infliximab compared to placebo at six months in the placebo-controlled portion of the trial; the results between the abatacept and infliximab groups were similar. Further improvement was observed at 12 months with abatacept. The ACR responses in Study VII were consistent with the DAS28 score. The open label period of Study VII provided an assessment of the ability of abatacept to maintain efficacy for subjects originally randomized to abatacept and the efficacy response of those subjects who were switched to abatacept following treatment with infliximab. The reduction from baseline in mean DAS28 score at day 365 (3.06) was maintained through day 729 (3.34) in those patients who continued with abatacept. In those patients who initially received infliximab and then switched to abatacept, there was improvement in the mean DAS28 score at day 729 (3.07) relative to day 365 (3.88).

At 6 months, the overall serious adverse events considered to be related to treatment was 1.9% (3 patients) in the abatacept group, 4.8% (8) in the infliximab group, and 2.7% (3) in the placebo group. The frequency of serious infections was 1.3% (2) in the abatacept group, 2.4% (4) in the infliximab group, and 0.9% (1) in the placebo group. The frequency of acute infusional adverse events was 5.1% (8) in the abatacept group, 18.2% (30) in the infliximab group, and 10.0% (11) in the placebo group. At 12 months, the overall serious adverse events considered to be related to treatment was 3.2% (5) in the abatacept group and 8.5% (14) in the infliximab group. The frequency of serious infections was 1.3% (2) in the abatacept group and 6.1% (10) in the infliximab group, with a total of 5 serious opportunistic infections in the infliximab group and none in the abatacept group. With regard to abnormal laboratory values at 6 months, antinuclear antibodies developed in 1.7% (2) of the abatacept group, 32.2% (38) of the infliximab group, and 4.9% (4) of the placebo group.

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Table 6: Disease Activity Score 28 (DAS28 ESR) Results in Study VII

DAS28 Response

Abatacept +MTX n = 150

Infliximab +MTX n = 156

Placebo +MTX n = 102

Mean Decrease Month 6 2.5 *** 2.3 *** 1.5

Month 12 2.9 2.3 NAa

Low Disease Activity Month 6 21% 26% 11%

Month 12 35% 22% NAa

Remission Month 6 11% 13% 3%

Month 12 19% 12% NAa

Note: Hypothesis tests performed only on the primary endpoint of DAS28 mean change at month 6. *** p<0.001 compared to placebo. a

Placebo administered for only six months. Study VIII: Safety of abatacept in patients with or without washout of previous TNF blocking agent therapy A study of open-label abatacept on a background of nonbiologic DMARDs was conducted in patients with active RA who had an inadequate response to previous (washout for at least 2 months; n=449) or current (no washout period; n=597) TNF-antagonist therapy (Study VIII, Study IM101064). The primary outcome, incidence of adverse events, serious adverse events, and discontinuations due to adverse events during 6 months of treatment, was similar between those who were previous and current TNF-antagonist users at enrollment, as was the frequency of serious infections. Results from Study VIII support the transition from TNF blocking agent therapy to ORENCIA therapy at the next scheduled dose of the TNF blocking agent therapy.

Study SC-I (IM101-174)

Study SC-I (IM101-174) was a randomized, double-blind, double-dummy non-inferiority study that compared the efficacy and safety of abatacept administered subcutaneously and intravenously in subjects with rheumatoid arthritis (RA), receiving background methotrexate (MTX) as the only DMARD, and experiencing an inadequate response to MTX (MTX-IR). The primary endpoint was ACR 20 at 6 months. The pre-specified non-inferiority margin of -7.5% allows for a maximum difference in point estimate of -2.1% in the ACR20 response of the SC ORENCIA® compared with IV ORENCIA® at month 6, which is not considered a clinically significant difference. As shown in Table 2, the study demonstrated non-inferiority of ORENCIA® administered subcutaneously vs intravenously with respect to ACR20 responses up to 6 months of treatment. The estimated difference between the 2 treatment groups (SC - IV) in the proportion of ACR 20 responders at Day 169 was 0.3% (95% CI: -4.2%, 4.8%). The proportion of subjects with an ACR 20 response at Day 169 was 76.0% in the SC abatacept group and 75.8% in the IV abatacept group (PP analysis). In Study SC-1, patients were randomized with stratification by body weight (<60 kg, 60 to 100 kg, > 100 kg) to receive ORENCIA® 125mg subcutaneous injections weekly, after a single loading dose

AU_PI_V5.0_15 August 2012 12

of ORENCIA® based on body weight or ORENCIA® intravenously on Days 1, 15, 29 and every four weeks thereafter. A total of 2472 subjects were enrolled in Study SC-I; 1457 were treated, 736 of subjects with SC abatacept and 721 were with IV abatacept. Subjects continued taking their current dose of MTX from the day of randomization. ACR response In Study SC-I, ORENCIA® administered subcutaneously (SC) was non-inferior relative to intravenous (IV) infusions of ORENCIA® with respect to ACR 20 responses up to 6 months of treatment. Patients treated with ORENCIA® subcutaneously also achieved similar ACR 50 and 70 responses as those patients receiving ORENCIA® intravenously at 6 months. No major differences in ACR responses were observed between intravenous and subcutaneous treatment groups in subgroups based on weight categories (less than 60 kg, 60 to 100 kg, and more than 100 kg; data not shown). The percent of ORENCIA®-treated patients achieving ACR 20, 50, and 70 responses and major clinical response (defined as achieving an ACR 70 response for a continuous 6-month period) in Study SC-I are shown in Table 2.

Health-related outcomes and quality of life In Study SC-I, improvement from baseline as measured by HAQ-DI at 6 months and over time was similar between subcutaneous and intravenous administration. Paediatric and Adolescent (Juvenile Idiopathic Arthritis) The safety and efficacy of ORENCIA® were assessed in a three-part study (IM101033, AWAKEN) including an open-label extension in children with polyarticular juvenile idiopathic arthritis (JIA). The study enrolled patients 6 to 17 years of age with moderately to severely active polyarticular JIA who had an inadequate response or intolerance to one or more DMARDs, such as MTX or TNF antagonists. Patients had a disease duration of approximately 4 years with active disease at study entry, as determined by baseline counts of active joints (mean, 16) and joints with loss of motion (mean, 16); patients had elevated C-reactive protein (CRP) levels (mean, 3.2 mg/dL) and ESR (mean, 32 mm/h). The patients enrolled had subtypes of JIA that at disease onset included Oligoarticular (16%), Polyarticular (64%; 20% were rheumatoid factor positive), and Systemic (20%). Patients with systemic JIA who had intermittent fever, rheumatoid rash, hepatosplenomegaly, pleuritis, pericarditis or macrophage activation syndrome within the prior 6 months were excluded. At study entry, 74% of patients were receiving MTX (mean dose, 13.2 mg/m2 per week) and remained on a stable dose of MTX (those not receiving MTX did not initiate MTX treatment during the study as this was not mandated as part of the protocol).

In Period A (open-label, lead-in), 190 patients (33% of which were under 12 years of age), were treated with ORENCIA®; patients received 10 mg/kg (maximum 1000 mg per dose) intravenously on days 1, 15, 29, and monthly thereafter. Response was assessed utilizing the ACR Paediatric30 definition of improvement, defined as ≥30% improvement in at least 3 of the 6 JIA core set variables and ≥30% worsening in not more than 1 of the 6 JIA core set variables. Patients demonstrating an ACR Pedi 30 response at the end of Period A were randomized into the double-blind phase (Period B) and received either ORENCIA® or placebo for 6 months or until disease flare. Disease flare was defined as a ≥30% worsening in at least 3 of the 6 JIA core set variables with ≥30% improvement in not more than 1 of the 6 JIA core set variables; ≥2 cm of worsening of the Physician or Parent Global Assessment was necessary if either was used as 1 of the 3 JIA core set variables used to define flare, and worsening in ≥2 joints was necessary if the number of active joints or joints with limitation of motion was used as 1 of the 3 JIA core set variables used to define flare.

At the conclusion of Period A, paediatricACR 30/50/70 responses were 65%, 50%, and 28%, respectively. PaediatricACR 30 responses were similar in all subtypes of JIA studied.

AU_PI_V5.0_15 August 2012 13

During the double-blind randomized withdrawal phase (Period B), ORENCIA®-treated patients experienced significantly fewer disease flares compared to placebo-treated patients (20% vs 53%); 95% CI of the difference (15%, 52%). The risk of disease flare among patients continuing on ORENCIA® was less than one third that for patients withdrawn from ORENCIA® treatment (hazard ratio=0.31, 95% CI [0.16, 0.59]). Among patients who received ORENCIA® throughout the study (Period A, Period B, and the open-label extension Period C), the proportion of paediatric ACR 30/50/70 responders has remained consistent for 31 months.

There is no clinical trial data for the use of Orencia® subcutaneous formulation in children, therefore its use in children cannot be recommended.

ORENCIA® has not been studied in children less than 6 years of age. The long-term effects of ORENCIA® therapy on skeletal, behavioural, cognitive, sexual, and immune maturation and development in children are unknown.

INDICATIONS ORENCIA® in combination with methotrexate is indicated for the treatment of moderate to severe active rheumatoid arthritis in adult patients who have had an insufficient response or intolerance to other disease modifying anti-rheumatic drugs (DMARDs), such as methotrexate or tumour necrosis factor (TNF) blocking agents. A reduction in the progression of joint damage and improvement in physical function have been demonstrated during combination treatment with ORENCIA® and methotrexate. ORENCIA in combination with methotrexate is also indicated in the treatment of severe, active and progressive rheumatoid arthritis in adults not previously treated with methotrexate.

ORENCIA® is indicated for reducing signs and symptoms in paediatric patients 6 years of age and older with moderately to severely active polyarticular juvenile idiopathic arthritis who have had an inadequate response to one or more disease-modifying anti-rheumatic drugs (DMARDs). ORENCIA® may be used as monotherapy or concomitantly with methotrexate (MTX). (There is no clinical trial data for the use of Orencia® subcutaneous formulation in children, therefore its use in children cannot be recommended.)

ORENCIA® should not be administered concurrently with other biological DMARDs (eg, TNF inhibitors, rituximab, or anakinra). CONTRAINDICATIONS ORENCIA® should not be administered to patients with known hypersensitivity to ORENCIA® or any of its components (see PRODUCT DESCRIPTION). ORENCIA should not be administered to patients with severe infections such as sepsis, abscesses, tuberculosis, and opportunistic infections.

PRECAUTIONS Combination with TNF blocking agents There is limited experience with the use of ORENCIA® in combination with TNF blocking agents. In placebo-controlled clinical trials in patients with adult RA, patients receiving concomitant intravenous ORENCIA® and TNF blocking agent therapy experienced more infections (24%) and serious infections (2.2%) compared to patients treated with only TNF blocking agents (19% and 0.8%, respectively). Concurrent therapy with ORENCIA® and a TNF blocking agent is not recommended.

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While transitioning from TNF blocking agent therapy to ORENCIA® therapy, patients should be monitored for signs of infection.

Other biologic RA therapy. There is insufficient experience to assess the safety and efficacy of ORENCIA administered concurrently with other biologic RA therapy, such as anakinra or rituximab, and therefore such use is not recommended.

Hypersensitivity Hypersensitivity reactions can be observed during treatment with any injectable protein. Such reactions have been reported with ORENCIA® intravenous administration in clinical trials, where patients were not required to be pretreated to prevent hypersensitivity reactions. The occurrence of anaphylaxis remained rare between the double blind trials and long-term open-label experience. (see ADVERSE EFFECTS – Infusion-related reactions and hypersensitivity reactions) Hypersensitivity was reported uncommonly. Other events potentially associated with drug hypersensitivity, such as hypotension, urticaria, and dyspnea, that occurred within 24 hours of ORENCIA® infusion were uncommon. Anaphylaxis or anaphylactoid reactions can occur after the first infusion and can be life-threatening. In postmarketing experience, a case of fatal anaphylaxis following the first infusion of ORENCIA® has been reported. If an anaphylactic or other serious allergic reaction occurs, administration of ORENCIA® should be stopped immediately with appropriate therapy instituted, and the use of ORENCIA® should be permanently discontinued.

Effects on the immune system The possibility exists for drugs that affect the immune system, including ORENCIA®, to affect vaccination responses and host defenses against infections and malignancies.

In a small study with healthy subjects ORENCIA® reduced the quantitative immune response (measured via antibody titer against the tetanus toxoid vaccine and pneumococci antigens). However the 2-fold increase in titer response to these antigens was not altered.

Infections Serious infections, including sepsis and pneumonia, have been reported in patients receiving ORENCIA®. Some of these infections have been fatal. Many of the serious infections have occurred in patients on concomitant immunosuppressive therapy which in addition to their underlying disease, could further predispose them to infections. Physicians should exercise caution when considering the use of ORENCIA® in patients with: a history of recurrent infections; underlying conditions which may predispose them to infections; or chronic, latent, or localized infections. Patients who develop a new infection while undergoing treatment with ORENCIA® should be monitored closely. Administration of ORENCIA® should be discontinued if a patient develops a serious infection. A higher rate of serious infections has been observed in adult RA patients treated with concurrent TNF blocking agents and ORENCIA®.

In placebo-controlled clinical studies in adults, of 1955 ORENCIA® patients and 989 placebo patients, two cases of tuberculosis were reported, one each in the ORENCIA® and placebo groups. When treating patients with therapies that modulate the immune system, it is appropriate to screen for tuberculosis infections, as was the case with patients in these clinical trials. ORENCIA® has not been studied in patients with a positive tuberculosis screen, and the safety of ORENCIA® in individuals with latent tuberculosis is unknown. Patients testing positive in tuberculosis screening, should be treated by standard medical practice prior to therapy with ORENCIA®.

Anti-rheumatic therapies have been associated with hepatitis B reactivation. Therefore, screening for viral hepatitis should be performed in accordance with published guidelines before starting therapy with ORENCIA®

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Malignancies In the placebo-controlled clinical trials in adult RA, the frequencies of malignancies in abatacept- and placebo-treated patients were 1.4% and 1.1%, respectively (see ADVERSE REACTIONS). Patients with known malignancies were not included in these clinical trials. In carcinogenicity studies in mice, an increase in lymphomas and mammary tumours were noted. The clinical significance of this observation is unknown (see CARCINOGENICITY). The potential role of ORENCIA® in the development of malignancies, including lymphoma, in humans is unknown.

Infusion-related reactions Infusion Related reactions can be observed during treatment with any injectable protein. Such reactions have been reported with ORENCIA® administration in clinical trials, where patients were not required to be pretreated to prevent hypersensitivity reactions. (see ADVERSE EFFECTS – Infusion-related reactions and hypersensitivity reactions) Immunizations Live vaccines should not be given concurrently with ORENCIA® or within 3 months of its discontinuation. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving ORENCIA®. No data are available on the effects of vaccinations in patients receiving ORENCIA®. Drugs that affect the immune system, including ORENCIA®, may blunt the effectiveness of some immunizations.

It is recommended that patients with juvenile idiopathic arthritis be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating ORENCIA® therapy. Autoimmune processes

There is a theoretical concern that treatment with ORENCIA might increase the risk for autoimmune processes, for example deterioration of multiple sclerosis. In the placebo-controlled clinical trials, abatacept treatment did not lead to increased autoantibody formation, such as antinuclear and anti-dsDNA antibodies, relative to placebo treatment

Interactions with other medicines Formal drug interaction studies have not been conducted with ORENCIA®.

The majority of patients in the RA placebo-controlled clinical trials received concomitant DMARDs, NSAIDs, and/or corticosteroids. Most patients were taking MTX. Other less frequently used concomitant DMARDs included chloroquine/hydroxychloroquine, sulfasalazine, and leflunomide. There is limited experience with abatacept in combination with other DMARDs such as azathioprine, gold and anakinra. Population pharmacokinetic analyses revealed that MTX, NSAIDs, corticosteroids, and TNF blocking agents did not influence abatacept clearance (see PHARMACOLOGY: PHARMACOKINETICS)

Concurrent administration of a TNF blocking agent with ORENCIA® has been associated with an increased risk of serious infections. Concurrent therapy with ORENCIA® and TNF blocking agents is not recommended.

There is insufficient experience to assess the safety and efficacy of ORENCIA® administered concurrently with anakinra or rituximab, and therefore such use is not recommended.

ORENCIA® has not been studied in combination with agents which deplete lymphocyte count. Such combination therapy could potentiate the effects of ORENCIA® on the immune system .

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Other Interactions Blood Glucose Testing. Parenteral drug products containing maltose can interfere with the readings of blood glucose monitors that use test strips with glucose dehydrogenase pyrroloquinolinequinone (GDH-PQQ). The GDH-PQQ based glucose monitoring systems may react with the maltose present in ORENCIA® for intravenous administration, resulting in falsely elevated blood glucose readings on the day of infusion. When receiving ORENCIA® for intravenous administration, patients that require blood glucose monitoring should be advised to consider methods that do not react with maltose, such as those based on glucose dehydrogenase nicotine adenine dinucleotide (GDH-NAD), glucose oxidase, or glucose hexokinase test methods.

Orencia® for subcutaneous administration does not contain maltose; therefore, patients do not need to alter their glucose monitoring.

Genotoxicity Abatacept was not genotoxic in in vitro tests for reverse gene mutation in bacteria, forward gene mutation in mammalian cells, and clastogenicity in human lymphocytes.

Carcinogenicity In a long term carcinogenicity study in mice, weekly subcutaneous abatacept treatment for up to 84-88 weeks resulted in increased incidences of malignant lymphomas at all doses (0.8 to 3-fold the human drug exposure based on AUC). Increased incidences of female mammary gland tumours were also observed at drug exposures (AUC) 2 to 3-fold the human exposure. While these tumours may be related to activation of murine leukaemia virus and mouse mammary tumour virus, respectively, by prolonged immumosuppression, there is no conclusive evidence to support this hypothesis.

Effects on fertility Fertility in rats was unaffected by abatacept doses of up to 200 mg/kg every 3 days (11-fold the human drug exposure based on AUC).

Use in pregnancy (Category C) Abatacept may affect the immune system in the fetus. Embryofetal development was unaffected by doses of up to 300 mg/kg/day in mice, 200 mg/kg/day in rats, and 200 mg/kg every 3 days in rabbits (approximately 29-fold the human drug exposure based on AUC). Abatacept was shown substantially to cross the placenta in rats, and minimally in rabbits. Offspring were unaffected by abatacept doses of up to 45 mg/kg given every 3 days to rats from early gestation through to the end of lactation (3-fold the human drug exposure based on AUC). With a dose of 200 mg/kg every 3 days (approximately 11-fold the human drug exposure based on AUC) female pups showed enhanced T cell dependent antibody responses and a single case (out of 20 pups) of thyroid chronic inflammation. Whether these findings indicate a potential for the development of autoimmune diseases in humans exposed in utero is uncertain. There are no adequate and well-controlled studies in pregnant women. The use of ORENCIA during pregnancy is not recommended.

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Use in lactation Abatacept has been shown to be present in rat milk and in the serum of suckling pups. It is not known whether abatacept is excreted in human milk or absorbed systemically after ingestion. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in breast-fed infants from abatacept, women on abatacept should not breast feed. The long half-life of abatacept should also be considered when discontinuing therapy.

PaediatricUse ORENCIA® is indicated for reducing signs and symptoms in paediatric patients 6 years of age and older with moderately to severely active polyarticular juvenile idiopathic arthritis who have had an inadequate response to one or more disease-modifying anti-rheumatic drugs (DMARDs). ORENCIA® may be used as monotherapy or concomitantly with methotrexate (MTX).

The safety and effectiveness of ORENCIA® in paediatric patients below 6 years of age have not been established. Therefore, ORENCIA® is not recommended for use in patients below the age of 6 years.

Safety and efficacy of ORENCIA® in paediatric patients for uses other than juvenile idiopathic arthritis have not been established.


The long-term effects of ORENCIA® therapy on skeletal, behavioural, cognitive, sexual, and immune maturation and development in children are unknown.

Non-clinical studies relevant for use in the paediatric population Studies in rats exposed to abatacept have shown immune system abnormalities including a low incidence of infections leading to death (juvenile rats) as well as inflammation of the thyroid and pancreas (both juvenile and adult rats). Studies in adult mice and monkeys have not demonstrated similar findings. The increased susceptibility to opportunistic infections observed in juvenile rats is likely associated with the exposure to abatacept prior to development of memory responses. The relevance of these results to humans greater than 6 years of age, where memory responses have more time to develop, is unknown.

Use in the elderly A total of 323 patients 65 years of age and older, including 53 patients 75 years and older, received ORENCIA® in clinical studies. Similar efficacy was observed in these patients and younger patients. The frequency of serious infection and malignancy among ORENCIA® -treated patients over age 65 was higher than for those under age 65. Because there is a higher incidence of infections and malignancies in the elderly population in general, caution should be used when treating the elderly.

Patients on controlled sodium diet This medicinal product contains 1.5mmol (or 34.5mg) sodium per maximum dose of 4 vials(0.375 mmol or 8.625 mg sodium per vial). To be taken into consideration when treating patients on a controlled sodium diet

Use in Patients with Chronic Obstructive Pulmonary Disease (COPD) COPD adult patients treated with ORENCIA developed adverse events more frequently than those treated with placebo, including COPD exacerbations, cough, rhonchi, and dyspnea. Use of ORENCIA in patients with rheumatoid arthritis and COPD should be undertaken with caution and such patients should be monitored for worsening of their respiratory status

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Subcutaneous Injections The first dose should be done under medical supervision. Patients can self inject after the treating physician/healthcare practitioner is assured that the patient’s and/or carer’s injection technique is satisfactory, and while providing medical follow-up as necessary. (see PREPARATION AND ADMINISTRATION INSTRUCTIONS FOR SUBCUTANEOUS INJECTION.)

Information for Patients

Patients should be provided the ORENCIA Patient Information leaflet and provided an opportunity to read it prior to each treatment session. Because caution should be exercised in administering ORENCIA to patients with active infections, it is important that the patient’s overall health be assessed at each visit and any questions resulting from the patient’s reading of the Patient Information be discussed.

ADVERSE EFFECTS Clinical trial experience in adult RA patients treated with intravenous ORENCIA® ORENCIA® has been studied in patients with active rheumatoid arthritis in placebo-controlled clinical trials (1955 patients with ORENCIA®, 989 with placebo). The trials had either a double-blind, placebo-controlled period of 6 months (258 patients with ORENCIA®, 133 with placebo) or 1 year (1697 patients with ORENCIA®, 856 with placebo). Most patients in these trials were taking methotrexate (81.9% with ORENCIA®, 83.3% with placebo). Other concomitant medications included: NSAIDs (83.9% with ORENCIA®, 85.1% with placebo); systemic corticosteroids (74.7% with ORENCIA®, 75.8% with placebo); non-biological DMARD therapy, most commonly chloroquine/hydroxychloroquine, leflunomide and/or sulfasalazine (26.9% with ORENCIA®, 32.1% with placebo); TNF blocking agents, mainly etanercept (9.4% with ORENCIA®, 12.3% with placebo); and anakinra (1.1% with ORENCIA®, 1.6% with placebo). In placebo-controlled clinical trials with ORENCIA®, adverse drug reactions (ADRs) (adverse events at least possibly causally-related to treatment) were reported in 52.2% of ORENCIA®-treated patients and 46.1% of placebo-treated patients. The most frequently reported adverse drug reactions (≥ 5%) among ORENCIA®-treated patients were headache and nausea. The proportion of patients who discontinued treatment due to ADRs was 3.4% for ORENCIA®-treated patients and 2.2% for placebo-treated patients.

Overall adverse events reported irrespective of consideration to causality to treatment in the placebo-controlled clinical trials in RA patients are listed in Table7.

The majority of these adverse events were mild to moderate and the severity was similar in patients that had previously taken traditional DMARDs, such as MTX, or biological therapies, such as TNF blocking agents (Table 8).

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Table 7: Overview of Adverse Events in Placebo-Controlled Clinical Trials in Rheumatoid Arthritis Patients

ORENCIA® (n=1955)

Percentage

Placebo (n=989)

Percentage All adverse events 88.8 85.1 Serious adverse events 14.0 12.5 Infections and infestations 54.1 48.7 Malignancies 1.4 1.1 Acute infusion-related events (reported within 1 hour of the start of the infusion)

9.8 6.7

Table 8: Intensity of Adverse Events in Double-Blind, Controlled Study Periods: Study IV vs Study III

Percent of Patients

Mild Moderate Severe Very Severe

Study IV, Inadequate Response to TNF Blocking Agent

ORENCIA® 61.2% 47.3% 8.1% 1.9%

Placebo 51.1% 42.1% 9.8 0.8%

Study III, Inadequate Response to MTX

ORENCIA® 75.1% 60.3% 15.2% 1.2%

Placebo 73.5% 55.3% 12.8% 0.9%

In general, adverse events are more common with biological agents as compared with other types of medications used in the management of rheumatoid arthritis.

Adverse drug reactions greater in frequency (difference >0.2%) in ORENCIA®-treated patients compared to placebo patients are listed below by system organ class and frequency (very common ≥10%; common ≥1% <10%; uncommon ≥0.1% <1%; rare ≥0.01% <0.1%).

Infections and infestations

Very Common: Upper respiratory tract infection (including tracheitis, nasopharyngitis)

Common: Lower respiratory tract infection (including, bronchitis), urinary tract infection, herpes infections (including herpes simplex, oral herpes and herpes zoster)), rhinitis

Uncommon: Tooth infection, infected skin ulcer, onchomycosis Neoplasms benign and malignant (including cysts and polyps)

Uncommon: Basal cell carcinoma

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Blood and the lymphatic system disorders Common: Leukopenia Uncommon: Thrombocytopenia

Psychiatric disorders Uncommon: Depression, anxiety, sleep disorder (including

insomnia) Nervous system disorders

Common: Headache, dizziness, paraesthesia

Eye disorders Common: Conjunctivitis Uncommon: Visual acuity reduced

Ear and labyrinth disorders Uncommon: Vertigo

Cardiac disorders Uncommon: Tachycardia, bradycardia, palpitations

Vascular disorders Common: Hypertension, flushing Uncommon: Hypotension, hot flush

Respiratory, thoracic and mediastinal disorders

Common: Cough Gastrointestinal disorders

Common: Abdominal pain, diarrhoea, nausea, dyspepsia, mouth ulceration, aphthous stomatitis

Uncommon: Gastritis Skin and subcutaneous tissue disorders

Common: Rash (including dermatitis), alopecia Uncommon: Increased tendency to bruise, , dry skin, hyperhidrosis,

erythema Musculoskeletal, connective tissue and bone disorders

Common: Pain in extremity Uncommon: Arthralgia

Reproductive system and breast disorders Uncommon: Amenorrhea, menorrhagia General disorders and administration site conditions

Common: Fatigue, asthenia Uncommon: Influenza like illness

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Investigations Common: Blood pressure increased, liver function test abnormal

(including transaminases increased) Uncommon: Blood pressure decreased, weight increased

Infections In the placebo-controlled trials, infections at least possibly related to treatment were reported in 23.2% of ORENCIA®-treated patients and 19.5% of placebo patients.

AEs reported in patients treated by abatacept intravenous or subcutaneous which did not occur with an excess incidence (i.e. the difference was not > 0.2%) over placebo but were considered to be medically relevant based on the overall clinical experience included sinusitis (common), Pelvic Inflammatory Disease (uncommon) and urosepsis (uncommon)

Serious infections at least possibly related to treatment were reported in 1.8% of ORENCIA®-treated patients and 1.0% of placebo patients. The most frequent (0.1-0.3%) serious infections at least possibly related to treatment reported with ORENCIA® were pneumonia, cellulitis, localized infection, urinary tract infection, bronchitis, diverticulitis, and acute pyelonephritis (see PRECAUTIONS). In double blind and open-label clinical trials in 4,149 patients treated with abatacept during 11,658 patient-years, the incidence rate of serious infections was 2.87 per 100 patient -years,

and the annualized incidence rate remained stable.

Malignancies In placebo-controlled clinical trials, malignancies were reported in 27 of 1955 ORENCIA®-treated patients observed during 1687 patient-years, and in 11 of 989 placebo-treated patients observed during 794 patient-years. In double-blind and open-label clinical trials in 4149 patients treated with ORENCIA® during 11,658 patient-years, (of which over 1,000 were treated with abatacept for over 5 years), the incidence rate of malignancy was 1.41 per 100 patient-years, and the annualised incidence rate remained stable. The incidence rates per 100 patient-years were 0.74 for non-melanomatous skin cancer, 0.57 for solid malignancies and 0.13 for hematologic malignancies. The most frequently reported solid organ cancer was lung cancer ( 0.15 per 100 patient-years), and the most common hematologic malignancy was lymphoma ( 0.07 per 100 patient-years). The incidence rate did not increase for malignancies overall, by major type (non-melanomatous skin cancer, solid tumors, and hematologic malignancies), or for individual tumor types in the double-blind and open label period compared to the double-blind experience. The type and pattern of malignancies reported during the open-label period of the trials were similar to those reported for the double-blind experience.

The incidence rate of observed malignancies was consistent with that expected in an age- and gender-matched rheumatoid arthritis population.

With regard to the general population, the observed and expected malignancies and the standardised incidence ratios are shown in Table 9.

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Table 9: Observed and Expected Malignancies and Standarised Incidence Ratios (SIRs) Compared with the General Populationa

Malignancy

Observedb Expectedc SIR (95% CI)d

Overall Solid Organ Malignancies

28 37.25 0.75 (0.50, 1.09)

Lung 11 4.88 2.25 (1.12, 4.03)

Breast 4 9.66 0.41 (0.11, 1.10)

Prostate 3 3.92 0.77 (0.15, 2.24)

Colon/Rectum 0 3.54 0 (0.00, 1.04)

Lymphoma 4 1.34 3.00 (0.81, 7.67)

a General Population Rate estimates from United States Surveillance and End Results (SEER). b Observed number in ORENCIA®-exposed patients in double-blind and open-label clinical trials.

c Based on General Population (SEER) rate estimates; adjusted for age and gender and takes into account duration of ORENCIA® exposure. d SIR -Standardised incidence ratio (Observed/Expected) 95% CI - confidence interval.

Infusion-related reactions and hypersensitivity reactions Infusion Related reactions can be observed during treatment with any injectable protein. Such reactions have been reported with ORENCIA® administration in clinical trials, where patients were not required to be pretreated to prevent hypersensitivity reactions.

Acute infusion reactions (within 1 hour of infusion) the incidence rate of 4.04 per 100 p-y. The annual incidence rate of acute-infusional events was elevated in the first year of exposure, decreased in the second, and then remained stable with increasing duration of exposure to abatacept. The 4 most common events contributing to this incidence rate per 100 p-y were dizziness (0.70), headache (0.69), hypertension (0.62), and nausea (0.40)). The frequencies of these 4 events were 1.9%, 1.8% 1.7% and 1.1%, respectively. Greater than 95% of all subjects with acute-infusional events were mild or moderate in intensity Peri-infusion reactions (upto 24hrs after infusion) the incidence rate was 11.63 per 100 p-y. The 4 most common events contributing this overall incidence rate per 100 p-y were headache (3.09), nausea (1.69), dizziness (1.56), and hypertension (1.16). Approximately 95% of all subjects with peri-infusional events had events that were mild or moderate in intensity. Adverse drug reactions in patients with chronic obstructive pulmonary disease (COPD) In Study V, there were 37 patients with COPD treated with ORENCIA® and 17 treated with placebo. The COPD patients treated with ORENCIA® developed adverse drug reactions more frequently than those treated with placebo (51.4% vs. 47.1%, respectively). Respiratory disorders occurred more frequently in ORENCIA®-treated patients than in placebo-treated patients (10.8% vs. 5.9%, respectively); these included COPD exacerbation, and dyspnea. A greater percentage of ORENCIA®- than placebo-treated patients with COPD developed a serious adverse reaction (5.4% vs. 0%), including COPD exacerbation (1 of 37 patients [2.7%]) and bronchitis (1 of 37 patients [2.7%]).

AU_PI_V5.0_15 August 2012 23

Autoimmune processes ORENCIA® therapy did not lead to increased formation of antinuclear or anti-double stranded DNA antibodies compared with placebo.

The incidence rate of autoimmune disorders remained stable during open-label experience (1.63 per 100 patient-years) compared to the double-blind experience (2.07 per 100 patient-years). The most frequently reported autoimmune-related disorder during the open-label experience was psoriasis.

Immunogenicity Antibodies directed against the ORENCIA® molecule were assessed by ELISA assays in 3,985 rheumatoid arthritis patients treated for up to 8 years with ORENCIA®. One hundred and eighty-seven of 3,877 patients developed anti-abatacept antibodies while on treatment. In patients assessed for anti-abatacept antibodies after discontinuation of ORENCIA® (>42 days after last dose), 103 of 1,888 (5.5%) were seropositive. Samples with confirmed binding activity to CTLA-4 were assessed for the presence of neutralizing antibodies. Twenty-two of 48 evaluable patients showed significant neutralizing activity. The potential clinical relevance of neutralizing antibody formation is not known. Overall, there was no apparent correlation of antibody development to clinical response or adverse events. However, the number of patients that developed antibodies was too limited to make a definitive assessment. Clinical experience in MTX-naive patients Study VI was an active-controlled clinical trial in MTX-naive patients. Data from Study VI were not integrated into the safety dataset described above in this section; however, the safety experience in MTX-naive patients was consistent with that described above in patients with an inadequate response to MTX or a TNF blocking agent. The adverse reaction profile observed in patients receiving MTX alone in Study VI was as expected, and the adverse reaction profile observed in patients receiving ORENCIA® plus MTX was similar to that in patients receiving MTX alone. Table 10 below lists the adverse drug reactions (ADRs - adverse events at least possibly causally related to treatment) occurring in ≥1% of patients treated with ORENCIA + MTX in AGREE (IM101023).

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Table 10 Adverse Drug Reactions (ADR’s) Occuring in ≥1% of Patients in the ORENCIA+MTX in AGREE (IM101023)

Less common Clinical Trial Adverse Drug Reactions (<1.0%)

ADRs reported in less than 1% of patients receiving ORENCIA + MTX in the AGREE Trial and not listed in Table 10 are listed below by body system. Blood and lymphatic system disorders: anaemia Ear and labyrinth disorders: vertigo Eye disorders: eye irritation, presbyopia Gastrointestinal disorders: vomiting, abdominal pain upper, dry mouth, dyspepsia, abdominal pain, gastritis, gastrointestinal haemorrhage, gastrointestinal pain, gingival ulceration, lip dry General disorders and administration site conditions: malaise, chest pain, asthenia, chest discomfort, axillary pain, chills, feeling hot, infusion related reaction, infusion site erythema, infusion site pain, sudden death Hepatobiliary disorders: hepatic function abnormal Immune system disorders: hypersensitivity Infections and infestations: gastroenteritis, tooth abscess, pneumonia, respiratory tract infection, sinusitis, tonsillitis, viral upper respiratory tract infection, acariasis, furuncle, genital herpes, tinea pedis, acarodermatitis, bacterial infection, bronchopneumonia, cystitis, ear infection, fungal rash, laryngitis, lung infection pseudomonal, rhinitis, sepsis, soft tissue infection, tinea versicolour, vaginal infection

Related Adverse Event (Preferred Term) ORENCIA + MTX n =

256 %

Placebo + MTX n = 253 %

infections and infestations bronchitis 3.9 1.2 nasopharyngitis 3.1 2.0 urinary tract infection 2.3 2.8 upper respiratory tract infection 2.3 2.4 oral herpes 2.0 1.2 pharyngitis 2.0 0.4 influenza 1.6 2.8 herpes zoster 1.2 1.2 gastrointestinal disorders nausea 4.3 4.3 mouth ulceration 1.6 0.4 diarrhoea 1.2 2.4 nervous system disorders headache 3.5 3.6 dizziness 3.5 2.4 investigations alanine aminotransferase increased 3.1 2.4 aspartate aminotransferase increased 2.0 1.6 weight increased 1.2 0 respiratory, thoracic and mediastinal disorders cough 2.7 1.6 general disorders and administration site conditions fatigue 1.2 1.2 vascular disorders hypertension 1.2 1.6

AU_PI_V5.0_15 August 2012 25

Injury, poisoning and procedural complications: contusion Investigations: transaminases increased, gamma-glutamyltransferase increased, blood alkaline phosphatase increased, blood pressure increased Metabolism and nutrition disorders: diabetes mellitus Musculoskeletal and connective tissue disorders: back pain, joint swelling, ligament disorder, musculoskeletal stiffness, pain in extremity, systemic lupus erythematosus Neoplasms benign, malignant and unspecified (incl cysts and polyps): lung neoplasm, skin papilloma Nervous system disorders: dysgeusia, paraesthesia Psychiatric disorders: depression, insomnia, nervousness Reproductive system and breast disorders: breast mass, breast pain Respiratory, thoracic and mediastinal disorders: nasal congestion, pharyngolaryngeal pain, rhinorrhoea, sinus congestion, dyspnoea exertional, nasal discomfort, nasal dryness Skin and subcutaneous tissue disorders: rash, alopecia, urticaria, acne, eczema, nail dystrophy, pruritus, psoriasis, skin lesion Vascular disorders: flushing, hyperaemia, hypotension

Clinical experience in Study VII (IM101043)

At 6 months, the overall serious adverse events considered to be related to treatment was 1.9% (3 patients) in the abatacept group, 4.8% (8) in the infliximab group, and 2.7% (3) in the placebo group. The frequency of serious infections was 1.3% (2) in the abatacept group, 2.4% (4) in the infliximab group, and 0.9% (1) in the placebo group. The frequency of acute infusional adverse events was 5.1% (8) in the abatacept group, 18.2% (30) in the infliximab group, and 10.0% (11) in the placebo group. At 12 months, the overall serious adverse events considered to be related to treatment was 3.2% (5) in the abatacept group and 8.5% (14) in the infliximab group. The frequency of serious infections was 1.3% (2) in the abatacept group and 6.1% (10) in the infliximab group, with a total of 5 serious opportunistic infections in the infliximab group and none in the abatacept group. With regard to abnormal laboratory values at 6 months, antinuclear antibodies developed in 1.7% (2) of the abatacept group, 32.2% (38) of the infliximab group, and 4.9% (4) of the placebo group.

Study VIII: Safety of abatacept in patients with or without washout of previous TNF blocking agent therapy A study of open-label abatacept on a background of nonbiologic DMARDs was conducted in patients with active RA who had an inadequate response to previous (washout for at least 2 months; n=449) or current (no washout period; n=597) TNF-antagonist therapy (Study VIII, Study IM101064). The primary outcome, incidence of adverse events, serious adverse events, and discontinuations due to adverse events during 6 months of treatment, was similar between those who were previous and current TNF-antagonist users at enrollment, as was the frequency of serious infections. Results from Study VIII support the transition from TNF blocking agent therapy to ORENCIA therapy at the next scheduled dose of the TNF blocking agent therapy.

AU_PI_V5.0_15 August 2012 26

Clinical trial experience in adult RA patients treated with subcutaneous Orencia®

In general, the adverse reactions in adult RA patients treated with subcutaneous abatacept were similar in type to those seen in patients treated with abatacept administered intravenously.

Study SC-I was a randomized, double-blind, double-dummy, non-inferiority study that compared the efficacy and safety of abatacept administered subcutaneously (SC) and intravenously (IV) in 1457 subjects with rheumatoid arthritis, receiving background methotrexate, and experiencing an inadequate response to MTX (MTX-IR). The safety experience and immunogenicity for Orencia®

administered subcutaneously was consistent with intravenous Studies I-VI. Due to the route of administration, injection site reactions and immunogenicity were evaluated and are discussed in the sections below.

A subgroup analysis, although limited by assessments involving small numbers and the lack of a comparator, did not reveal any unexpected safety concerns. The finding that more AEs were reported subjects >100 kg both for IV and SC abatacept may reflect small numbers of subjects in some subgroups and differences in exposure.

Injection Site Reactions in Adult RA Patients Treated with SC Abatacept Study SC-I compared the safety of abatacept including injection site reactions following subcutaneous or intravenous administration. The overall frequency of injection site reactions was 2.6% (19/736) and 2.5% (18/721) for the SC abatacept group and the IV abatacept group (SC placebo), respectively. All injection site reactions were described as mild to moderate (hematoma, pruritus, or erythema) and generally did not necessitate drug discontinuation.

Immunogenicity in Adult RA Patients Treated with SC Abatacept Study SC-I compared the immunogenicity to abatacept following subcutaneous or intravenous administration. The overall immunogenicity frequency to abatacept was 1.1% (8/725) and 2.3% (16/710) for the subcutaneous and intravenous groups, respectively. The rate is consistent with previous experience, and there was no effect of immunogenicity on pharmacokinetics, safety, or efficacy.

Immunogenicity and Safety of SC Abatacept Administration as Monotherapy without an IV Loading Dose Study SC-II was conducted to determine the effect of monotherapy use of ORENCIA® on immunogenicity following subcutaneous administration without an intravenous load in 100 RA patients, who had not previously received abatacept or other CTLA4Ig, who received either subcutaneous ORENCIA® plus methotrexate (n=51) or subcutaneous ORENCIA® monotherapy (n=49). No patients in either group developed anti-product antibodies after 4 months of treatment. The safety observed in this study was consistent with that observed in the other subcutaneous studies.

AU_PI_V5.0_15 August 2012 27

Immunogenicity and Safety of SC Orencia® upon Withdrawal (Three Months) and Restart of Treatment Study SC-III in the subcutaneous program was conducted to investigate the effect of withdrawal (three months) and restart of ORENCIA® subcutaneous treatment on immunogenicity in RA patients treated concomitantly with methotrexate. One hundred sixty-seven patients were enrolled in the first 3-month treatment period and responders (n=120) were randomized to either subcutaneous ORENCIA® or placebo for the second 3-month period (withdrawal period). Patients from this period then received open-label ORENCIA® treatment in the final 3-month period of the study (period 3). At the end of the withdrawal period, 0/38 patients who continued to receive subcutaneous ORENCIA® developed anti-product antibodies compared to 7/73 (9.6%) of patients who had subcutaneous ORENCIA® withdrawn during this period. Half of the patients receiving subcutaneous placebo during the withdrawal period received a single intravenous infusion of ORENCIA® at the start of period 3 and half received intravenous placebo prior to reinitiating subcutaneous ORENCIA® in Period 3. At the end of period 3, when all patients again received subcutaneous ORENCIA®, the immunogenicity rates were 1/38 (2.6%) in the group receiving subcutaneous ORENCIA® throughout, and 2/73 (2.7%) in the group that had received placebo during the withdrawal period. Upon reinitiating therapy, there were no injection reactions and no differences in response to therapy in patients who were withdrawn from subcutaneous therapy for up to 3 months relative to those who remained on subcutaneous therapy, whether therapy was reintroduced with or without an intravenous loading dose. The safety observed in this study was consistent with that observed in the other studies.

Postmarketing experience Adverse reactions have been reported during the post-approval use of ORENCIA®. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to ORENCIA®. Based on the postmarketing experience with ORENCIA® in adult rheumatoid arthritis (RA) patients, the adverse event profile of ORENCIA® does not differ from that listed/discussed above in adults.

Laboratory findings Based on the results of clinical studies, no special laboratory evaluations are necessary in addition to careful medical management and supervision of patients.

Clinical Trial experience in Paediatric and Adolescent patients treated with intravenous ORENCIA®

In general, the adverse events in paediatric patients were similar in frequency and type to those seen in adult patients (see PRECAUTIONS AND ADVERSE EFFECTS).

ORENCIA® has been studied in 190 paediatric patients; 6 to 17 years of age, with polyarticular juvenile idiopathic arthritis (see CLINICAL TRIAL EFFICACY INFORMATION). Overall frequency of adverse events in the 4-month, lead-in, open-label period of the study was 70%; infections occurred at a frequency of 36%. The most common infections were upper respiratory tract infection and nasopharyngitis. The infections resolved without sequelae, and the types of infections were consistent with those commonly seen in outpatient paediatric populations. Other events that occurred at a prevalence of at least 5% were headache, nausea, diarrhea, cough, pyrexia, and abdominal pain.

A total of 6 serious adverse events (acute lymphocytic leukemia, ovarian cyst, varicella infection, disease flare [2], and joint wear) were reported during the initial 4 months of treatment with ORENCIA®

For the 122 patients who responded in the lead-in period and entered the placebo-controlled, 6-month, withdrawal phase, there were no serious adverse events in 60 ORENCIA-treated patients

AU_PI_V5.0_15 August 2012 28

and 3 serious adverse events in 2 of the 62 placebo-treated patients (hematoma in one patient, varicella and encephalitis in the other).

Of the 190 patients with JIA treated with ORENCIA® in this study, one (0.5%) patient discontinued due to non-consecutive infusion reactions, consisting of bronchospasm and urticaria. During Periods A, B, and C, acute infusion-related reactions occurred at a frequency of 4%, 2%, and 3%, respectively, and were consistent with the types of events reported in adults.

Upon continued treatment in the open-label extension period, 27.5% (42/153) of patients discontinued treatment, and the types of adverse events were similar in frequency and type to those seen in adult patients, except for a single 14 year old patient diagnosed with temporal lobe epilepsy secondary to multiple sclerosis while on open-label treatment. The subject was reported to have a probable seizure four days after the 12th infusion of abatacept. The subject had no known personal or family history of multiple sclerosis prior to study entry. This has been the only case of MS in the JIA study with abatacept and there is no evidence to date that there is a increased risk of MS or other demyelinating events due to abatacept treatment.

Adverse events regardless of causality occurring in ≥5% of pediatric patients receiving ORENCIA®

in period B (double-blind phase) of the three part study conducted in paediatric and adolescent patients with polyarticular JIA are listed in Table 11 below by system organ classification. All adverse events listed below fall into the frequency category of common (≥1% <10%), as defined above for adult RA.

Table 11: Adverse Events in Placebo-Controlled Trials (regardless of causality) at ≥ 5% for Period B(double-blind phase)

System Organ Classification / Preferred Term

ORENCIA®

n (%) Placeboa

n (%)

Number treated 60 (100) 62 (100)

Infections and infestations

Influenza 5 (8.3) 4 (6.5)

Bacteriuria 4 (6.7) 0

Nasopharyngitis 4 (6.7) 3 (4.8)

Upper respiratory tract infection

4 (6.7) 5 (8.1)

Gastroenteritis 3 (5.0) 1 (1.6)

Sinusitis 3 (5.0) 2 (3.2)

Gastrointestinal disorders

Abdominal pain 3 (5.0) 1 (1.6)

General disorders and administration site conditions

Pyrexia 4 (6.7) 5 (8.1)

Nervous system disorders

Headache 3 (5.0) 1 (1.6) a Preceding the double-blind phase of the study (Period B), all patients were treated with ORENCIA® for 4 months in the open-label, lead-in phase (Period A). At the conclusion of Period A, patients who exhibited a predefined clinical response were randomized into one of 2 arms (in Period B), and either continued on ORENCIA® or withdrew from

AU_PI_V5.0_15 August 2012 29

ORENCIA® to receive placebo. See CLINICAL TRIAL EFFICACY INFORMATION: Paediatric and Adolescent (Juvenile Idiopathic Arthritis).

Clinical Trial Adverse Drug Reactions (< 5%) ADR’s reported in less than 5% for Period B (double-blind) for patients receiving ORENCIA® in the paediatric clinical trials are listed below by body system. Each ADR was a single ADR case yielding an incidence of 1.7%, no ADR with a frequency of less than 1% was reported.

Infections and Infestations: Sinusitis, influenza, rhinitis, tinea versicolour, upper respiratory tract infection, bacteriuria, otitis externa

Gastroinintestinal disorders: Abdominal pain, nausea, aphthous stomatitis

Skin and subcutaneous tissue disorders: Pityriasis, skin lesion

Nervous system disorders: headache

Renal and urinary disorders: Leukocyturia

Vascular disorders: Hypotension

Infections Adverse events of infections were reported in 36% of patients in the 4-month, lead-in, open-label period. The most common infections were upper respiratory tract infections [14 (7.4%)] and nasopharyngitis [11 (5.8%)]. Other than upper respiratory tract infections and nasopharyngitis, few infectious adverse events were reported. No pneumonias or opportunistic infections were observed.

During the double-blind phase, adverse events of infections were reported in the abatacept and placebo groups [45% and 44%]; influenza 5 [8.3%] vs 4 [6.5%], bacteriuria 4 [6.7%] vs 0 [0%], nasopharyngitis 4 [6.7%] vs 3 [4.8%], and upper respiratory tract infections 4 [6.7%] vs 5 [8.1%], were the most frequently reported events.

Infusion-related Reactions In the open-label lead-in phase of the study, eight (4.2%) patients experienced acute infusional adverse events; all but one was mild in intensity and none was serious. Most infusional adverse events were reported as single events in one patient each with no recurrences; headache and dizziness occurred in four and two patients, respectively. During the double-blind phase, acute infusional adverse events were reported in 1.7% and 3.2% of the abatacept and placebo groups, respectively; all were either mild or moderate in intensity and none were serious.

Autoantibodies In Period A of the paediatric clinical trial, 10.6% of ORENCIA treated patients that had negative antinuclear antibody titers at baseline had positive titers at Day 113. In Period B, 5.9% of ORENCIA treated patients and 4.0% of placebo patients that had negative antinuclear antibody titers at baseline had positive titers at Day 169.

In Period A, newly detected anti-dsDNA antibodies were observed in 6.2% of ORENCIA treated patients at Day 113. In Period B, newly detected anti-dsDNA antibodies were observed in 2.3% of ORENCIA treated patients and 0% of placebo patients at Day 169.

Immunogenicity Antibodies directed against the entire abatacept molecule or to the CTLA-4 portion of abatacept were assessed by ELISA assays in patients with polyarticular JIA following repeated treatment with ORENCIA®. The rate of seropositivity while patients were receiving abatacept therapy was 0.5% (1/189) during Period A; 13.0% (7/54) during Period B; and

AU_PI_V5.0_15 August 2012 30

11.4% (17/149) during Period C. For patients in Period B who were randomized to placebo (therefore withdrawn from therapy for up to 6 months) the rate of seropositivity was 40.7% (22/54). Anti-abatacept antibodies were generally transient and of low titer. The absence of concomitant methotrexate (MTX) did not appear to be associated with a higher rate of seropositivity in Period B placebo recipients. The presence of antibodies was not associated with adverse events or infusional reactions, or with changes in efficacy or serum abatacept concentrations. Of the 54 patients withdrawn from ORENCIA® during the double-blind period for up to 6 months, none had an infusion reaction upon re-initiation of ORENCIA®.

Malignancies

A single case of acute lymphocytic leukaemia was reported in the paediatric trial. No other malignancies were reported

DOSAGE AND ADMINISTRATION For adult patients with RA, ORENCIA® may be administered as an intravenous (IV) infusion or a subcutaneous (SC) injection. Methotrexate, other non-biologic DMARDs, corticosteroids, salicylates, nonsteroidal anti-inflammatory drugs (NSAIDs), or analgesics may be used during treatment with ORENCIA®.

IV dosing regimen Orencia® IV should be administered as a 30-minute intravenous infusion utilizing the weight range-based dosing specified in Table 12. Following the initial IV administration, an intravenous infusion should be given at 2 and 4 weeks after the first infusion and every 4 weeks thereafter.

Table 12: Dose of ORENCIA® for Intravenous Infusion in Adult RA

Body Weight of Patient Dose

Number of Vialsa

< 60 kg 500 mg 2

60 to 100 kg 750 mg 3

> 100 kg 1 gram 4

a Each vial provides 250 mg of abatacept for administration.

For paediatric juvenile idiopathic arthritis, a dose calculated based on each patient’s body weight is used (see Paediatric and adolescent).

SC dosing regimen

Following a single intravenous loading dose (as per body weight categories listed in Table 12), the first 125 mg subcutaneous injection of ORENCIA should be given within a day, followed by 125 mg subcutaneous injections once weekly.

Patients who are unable to receive an infusion may initiate weekly injections of subcutaneous ORENCIA without an intravenous loading dose.

AU_PI_V5.0_15 August 2012 31

Patients transitioning from ORENCIA intravenous therapy to subcutaneous administration should administer the first subcutaneous dose instead of the next scheduled monthly intravenous dose.

Hypersensitivity Reactions

Hypersensitivity reactions are uncommon with the infusion of ORENCIA, however these may occur. To minimize the incidence of hypersensitivity reactions, the patient should be monitored closely before and after ORENCIA administration. Should any such reaction occur, then appropriate responses and treatments are to be initiated. The necessary equipment, treatments and procedures sufficient to initiate management of acute infusion reactions (anaphylaxis) should be in place.

The risk of hypersensitivity reactions including anaphylaxis and how they are managed should be discussed with the patient by the prescriber prior to the patient receiving ORENCIA, so that the patient is aware of such risks and has an understanding of these risks.

Renal impairment, hepatic impairment ORENCIA® has not been studied in theses patient populations. No dose recommendations can be made.

Paediatric and adolescent Juvenile Idiopathic Arthritis. The recommended dose of ORENCIA® for patients 6 to 17 years of age with juvenile idiopathic arthritis who weigh less than 75 kg is 10 mg/kg calculated based on the patient’s body weight at each administration. Paediatric patients weighing 75 kg or more should be administered ORENCIA® following the adult dosing regimen, not to exceed a maximum dose of 1000 mg. ORENCIA® should be administered as a 30-minute intravenous infusion. Following the initial administration, ORENCIA® should be given at 2 and 4 weeks after the first infusion and every 4 weeks thereafter. Any unused portions in the vials must be immediately discarded.


Use in the elderly No dose adjustment is required (see PRECAUTIONS).

Concomitant therapy Methotrexate, other non-biologic DMARDs, corticosteroids, salicylates, nonsteroidal anti-inflammatory drugs (NSAIDs), or analgesics may be used during treatment with ORENCIA®.

AU_PI_V5.0_15 August 2012 32

PREPARATION AND ADMINISTRATION INSTRUCTIONS FOR INTRAVENOUS INFUSION Use aseptic technique. ORENCIA® is provided as a lyophilized powder in preservative-free, single-use vials. Each vial of ORENCIA® must be reconstituted with 10 mL of sterile water for injection, BP. Immediately after reconstitution, the product must be further diluted to 100 mL with 0.9% sodium chloride injection, BP. To reduce microbiological hazard, use as soon as practicable after dilution. If storage is necessary hold at 2 – 8 ºC for not more than 24 hours.

1) Each ORENCIA® vial provides 250 mg of abatacept for administration. 2) Reconstitute the ORENCIA® powder in each vial with 10 ml of sterile water for injection BP,

USING ONLY the SILICONE-FREE DISPOSABLE SYRINGE PROVIDED WITH EACH VIAL and an 18-21-gauge needle. Remove the flip-top from the vial and wipe the top with an alcohol swab. Insert the syringe needle into the vial through the center of the rubber stopper and direct the stream of sterile water for injection BP, to the glass wall of the vial. Do not use the vial if the vacuum is not present. To minimize foam formation in solutions of ORENCIA®, the vial should be rotated with gentle swirling until the contents are completely dissolved. Avoid prolonged or vigorous agitation. Do not shake. Upon complete dissolution of the lyophilized powder, the vial should be vented with a needle to dissipate any foam that may be present. The solution should be clear and colorless to pale yellow. Do not use if opaque particles, discoloration, or other foreign particles are present. After reconstitution, the concentration of abatacept in the vial will be 25mg/mL

3) The reconstituted ORENCIA® solution must be further diluted to 100 ml as follows. From a 100 ml infusion bag or bottle, withdraw a volume of 0.9% sodium chloride injection BP, equal to the volume of the reconstituted ORENCIA. Slowly add the reconstituted ORENCIA® solution from each vial to the infusion bag or bottle, USING ONLY the SILICONE-FREE DISPOSABLE SYRINGE PROVIDED WITH EACH VIAL. Gently mix. DO NOT SHAKE THE BAG OR BOTTLE. The final concentration of abatacept in the bag or bottle will depend upon the amount of drug added, but will be no more than 10mg/mL.Any unused portion in the vials must be immediately discarded.

4) Prior to administration, the ORENCIA® solution should be inspected visually for particulate matter and discolouration. Discard the solution if any particulate matter or discolouration is observed.

5) The entire, fully diluted ORENCIA® solution should be administered over a period of 30 minutes and must be administered with an infusion set and a sterile, non-pyrogenic, low-protein-binding filter (pore size of 0.2 to 1.2 µm).

6) ORENCIA® should not be infused concomitantly in the same intravenous line with other agents. No physical or biochemical compatibility studies have been conducted to evaluate the co-administration of ORENCIA® with other agents.

7) EACH VIAL OF ORENCIA® IS FOR SINGLE USE IN ONE PATIENT ONLY. DISCARD ANY RESIDUE.

If the SILICONE-FREE DISPOSABLE SYRINGE is dropped or becomes contaminated, use a new SILICONE-FREE DISPOSABLE SYRINGE from inventory. For information on obtaining additional SILICONE-FREE DISPOSABLE SYRINGES, contact Bristol-Myers Squibb Australia 1800-RENCIA or contact Bristol-Myers Squibb Australia 1800-067567.

AU_PI_V5.0_15 August 2012 33

PREPARATION AND ADMINISTRATION INSTRUCTIONS FOR SUBCUTANEOUS INJECTION ORENCIA® Injection, 125 mg/syringe is not intended for IV infusion.

ORENCIA® Injection is intended for use under the guidance of a physician or healthcare practitioner. The first dose should be done under medical supervision. Patients can self inject after the treating physician/healthcare practitioner is assured that the patient’s and/or carer’s injection technique is satisfactory, and while providing medical follow-up as necessary.

After training in subcutaneous injection technique, the patient may self-inject ORENCIA® Patients should be instructed to follow the directions provided in the Patient/Caregiver Instructions for Use section for additional details on medication administration.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use ORENCIA® prefilled syringes exhibiting particulate matter or discoloration. ORENCIA® should be clear and colorless to pale yellow. EACH PRE-FILLED SYRINGE OF ORENCIA® IS FOR SINGLE USE IN ONE PATIENT ONLY. DISCARD ANY RESIDUE.

Patients using ORENCIA® for subcutaneous administration should be instructed to inject the full amount in the syringe (1.0 mL), which provides 125 mg of ORENCIA®, according to the directions provided in the Patient/Caregiver Instructions for Use section.

Injection sites should be rotated and injections should never be given into areas where the skin is tender, bruised, red, or hard.

OVERDOSE Doses up to 50 mg/kg have been administered intravenously without apparent toxic effect. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions and appropriate symptomatic treatment instituted.

In the event of an overdose or poisoning contact the Poisons Information Centre on 131126.

PRESENTATION For Intravenous Infusion ORENCIA® is a lyophilized powder for intravenous infusion; it is supplied as an individually packaged, single-use vial with a silicone-free disposable syringe. All components of the syringe are latex-free. The product is available in the strength of 250 mg of abatacept in a 15-mL vial.

For Subcutaneous Injection ORENCIA® (abatacept) injection solution for subcutaneous administration is supplied either in a 1mL single-dose disposable prefilled glass syringe (with a passive needle safety guard) or as a 1mL single-dose disposable prefilled glass syringe with flange extender. The product is available in the strength of 125 mg of abatacept and is provided in a pack of 4 1mL single-dose prefilled syringes.

AU_PI_V5.0_15 August 2012 34

Storage and Stability conditions:

ORENCIA® lyophilized powder must be refrigerated at 2°C to 8°C. For storage of the fully diluted ORENCIA solution, (see PREPARATION AND ADMINISTRATION)

ORENCIA® (abatacept) injection solution for subcutaneous administration must be refrigerated at 2°C to 8°C. DO NOT FREEZE.

Do not use beyond the expiration date.

Protect the vials and prefilled syringes from light by storing in the original package until time of use.

Poisons Schedule: S4

DISTRIBUTED BY: Bristol-Myers Squibb Australia Pty Ltd 556 Princes Highway NOBLE PARK VIC 3174 AUSTRALIAN REGISTRATION NUMBERS: ORENCIA® lyophilized powder for intravenous infusion: AUST R 130100 ORENCIA® injection solution for subcutaneous administration with needle guard: AUST R 177174 ORENCIA® injection solution for subcutaneous administration: AUST R 177176 SYRINGE: AUST R 12743 Date of first Inclusion in the ARTG: 27 September 2007 Date of Most Recent Amendment: 15 August 2012

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